The ABC superfamily is comprised of myriad transmembrane proteins involved in the transport of vitamins, peptides, ions, sugars and amino acids (Higgins, C. F. ABC-transporters: from microorgansism to man. Annu. Rev. Cell Biol. 8, 67-113 (1992)). A subset of the superfamily contains four closely related proteins (ABC1, ABC2, ABC3 and ABCR) (Luciani, M. F., Denizot, F., Savar, S., Mattei, M. G. & Chimini, G. Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics 21, 150-159 (1994). Connors, T. D. et al. The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3. Genomics 39, 231-234 (1997). Allikmets, R. et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet. 15, 236-246 (1997)). The protein structure of this subfamily consists of two halves joined by a linker region, each with six transmembrane domains and an ATP-binding cassette site. Several diseases are the result of a dysfunctional ABC transporter--cystic fibrosis, Zellweger syndrome, adrenoleukodystrophy, multidrug resistance and Stargardt macular dystrophy--though the underlying molecular mechanism of the disease is seldom known (Allikmets, R. et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet. 15, 236-246 (1997). Riordan, J. R. et al. Identification of the cystic-fibrosis gene--cloning and characterization of complementary-DNA. Science 245, 1066-1072 (1989). Gartner, J., Moser, H. & Valle, D. Mutations in the 70k peroxisomal membrane-protein gene in Zellweger syndrome. Nature Genet. 1, 16-23 (1992). Mosser, J. et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361, 726-730 (1993). Gottesman, M. M. & Patan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385-428).
The relationship between TD (Tangier disease), FHA (familial hypoalphalipoproteinemia) and mutation in the human ABC1 gene has recently been established by positional cloning of hABC1 from several different families bearing TD or FHA (Bodzioch, M. et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nature Genet. 22, 347-351 (1999). Brooks-Wilson, A. et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature Genet. 22, 336-345. Rust, S. et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nature Genet. 22, 352-355 (1999)). In each case, point mutations, deletions or frameshifts creates a non-functional or truncated hABC1 protein. Individuals suffer from reduced or absent HDL-C and lower serum cholesterol and may exhibit discolored tonsils, enlarged spleen and lymph nodes, corneal clouding and neuropathy due to deposition of cholesteryl esters. In other cholesterol metabolic diseases such as Apo A-I deficiency, LCAT deficiency and Fish Eye disease, HDL-C is also reduced but serum cholesterol levels remain normal (Assmann, G., von Eckardstein, A. & Brewer, H. B. Jr Familial high density lipoprotein deficiency: Tangier disease. in The Metabolic and Molecular Basis of Inherited Disease (eds Scriver, C. R. et al.) 2053-2072 (McGraw-Hill, New York, 1995)). Low levels of HDL-C usually indicate a high-risk factor for coronary heart disease. Interestingly, the loss of HDL-C in TD patients does not generally cause predisposition to coronary heart disease.
Tangier disease is exceedingly rare, with only 40 reported families worldwide exhibiting the trait. As such, except for the absence of HDL-C, it is difficult to evaluate which symptoms may be directly attributed to a dysfunctional ABC1 transporter. The murine model of Tangier disease, which is described here, confirms the association of ABC1 with TD and exhibits other phenotypes which have not yet been described in humans. The model may further elucidate why the loss of HDL-C does not directly cause coronary heart disease in TD patients.
The human ATP-binding cassette transporter 1 (hABC1), a member of the ABC superfamily, has recently been cloned and analyzed. Frameshift mutations and single base-pair deletions resulting in truncation of hABC1 have been described and linked to familial HDL deficiency (familial hypoalphalipoproteinemia or FHA) and Tangier disease (TD). Both diseases are characterized by the lowering or lack of HDL-C. Low serum cholesterol, splenomegaly, enlarged lymph nodes and the deposition of cholesteryl esters in the reticuloendothelial system are also associated with TD.